SUMOylation Inhibitor TAK-981 Alleviates Hallmark Features of Preeclampsia Related to High Glucocorticoid Exposure by Inhibiting Placental Oxidative Stress in Rats

SUMOylation may be involved in preeclampsia (PE) progression. We aimed to investigate the roles of SUMOylation in PE and its underlying mechanism using animal and cell models. A rat PE model was established by dexamethasone (DEX) treatment from pregnancy day 7.5-17.5. HTR8 and BeWo trophoblasts were used as cell models. Placental RNA-seq analysis coupled with Western blotting showed upregulated SUMOylation in placentas of DEX-treated rats. SUMOylation inhibitor TAK-981 treatment robustly alleviated PE-like features including reduced blood pressure and improved renal injury, fetal weight, spiral artery remodeling and placental blood flow in DEX-treated rats. DEX increased SUMOylation in HTR8 and BeWo cells. TAK-981 reversed DEX-induced dysfunction in HTR8 and BeWo cells, such as migration, invasion and syncytialization. Mass spectrum analysis of SUMO1 immunoprecipitation coupled with functional validation showed that SUMOylated proteins related to oxidative stress caused by DEX were reversed by TAK-981 in cultured trophoblasts. TAK-981 mitigated placental oxidative stress in DEX-treated rats. GEO database combined with Western blotting showed upregulated SUMOylation in human placentas with PE. Our findings indicate that protein SUMOylation is one of the key events in PE, particularly in that associated with high glucocorticoid exposure. Targeting placental SUMOylation might be a promising therapeutic strategy for PE.